Application and Structural Analysis of Triazole‐Bridged Disulfide Mimetics in Cyclic Peptides
Ruthenium‐catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5‐disubstituted 1,2,3‐triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied...
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| Veröffentlicht in: | Angewandte Chemie International Edition 2020-07, Vol.59 (28), p.11273-11277 |
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| creator | White, Andrew M. Veer, Simon J. Wu, Guojie Harvey, Peta J. Yap, Kuok King, Gordon J. Swedberg, Joakim E. Wang, Conan K. Law, Ruby H. P. Durek, Thomas Craik, David J. |
| description | Ruthenium‐catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5‐disubstituted 1,2,3‐triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross‐linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor‐1. NMR and X‐ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD |
| doi_str_mv | 10.1002/anie.202003435 |
| format | Article |
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Made to measure: Disulfide mimetics are an important tool to overcome the redox instability of disulfide‐rich peptides for therapeutic application. The installation and structural characterisation of a triazole motif (blue) is reported that provides exceptional mimicry of disulfide linkages (yellow). This approach was demonstrated for a series of backbone‐cyclic serine protease inhibitors.</description><edition>International ed. in English</edition><identifier>ISSN: 1433-7851</identifier><identifier>EISSN: 1521-3773</identifier><identifier>DOI: 10.1002/anie.202003435</identifier><identifier>PMID: 32270580</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Alkynes ; Amino Acid Sequence ; Backbone ; Crystallography ; Crystallography, X-Ray ; Cyclization ; Cycloaddition ; disulfide mimetics ; Disulfides - chemistry ; inhibitors ; Linkages ; Molecular Mimicry ; NMR ; Nuclear magnetic resonance ; Nuclear Magnetic Resonance, Biomolecular ; Peptides ; Peptides, Cyclic - chemistry ; peptidomimetics ; Protease inhibitors ; Proteinase inhibitors ; Ruthenium ; Ruthenium - chemistry ; Serine ; Serine proteinase ; Structural analysis ; Sunflowers ; triazole bridges ; Triazoles ; Triazoles - chemistry ; Trypsin ; Trypsin inhibitors</subject><ispartof>Angewandte Chemie International Edition, 2020-07, Vol.59 (28), p.11273-11277</ispartof><rights>2020 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4505-964f98ded34bac50cf2c41116ddbeb568a853392f9447e0f4bf8b4bee30224353</citedby><cites>FETCH-LOGICAL-c4505-964f98ded34bac50cf2c41116ddbeb568a853392f9447e0f4bf8b4bee30224353</cites><orcidid>0000-0002-7973-7632 ; 0000-0001-5592-5789 ; 0000-0003-4243-8660 ; 0000-0003-0686-227X ; 0000-0003-4735-6242 ; 0000-0003-0007-6796 ; 0000-0002-9481-1079 ; 0000-0002-9409-5287 ; 0000-0002-7041-9937</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fanie.202003435$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fanie.202003435$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32270580$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>White, Andrew M.</creatorcontrib><creatorcontrib>Veer, Simon J.</creatorcontrib><creatorcontrib>Wu, Guojie</creatorcontrib><creatorcontrib>Harvey, Peta J.</creatorcontrib><creatorcontrib>Yap, Kuok</creatorcontrib><creatorcontrib>King, Gordon J.</creatorcontrib><creatorcontrib>Swedberg, Joakim E.</creatorcontrib><creatorcontrib>Wang, Conan K.</creatorcontrib><creatorcontrib>Law, Ruby H. P.</creatorcontrib><creatorcontrib>Durek, Thomas</creatorcontrib><creatorcontrib>Craik, David J.</creatorcontrib><title>Application and Structural Analysis of Triazole‐Bridged Disulfide Mimetics in Cyclic Peptides</title><title>Angewandte Chemie International Edition</title><addtitle>Angew Chem Int Ed Engl</addtitle><description>Ruthenium‐catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5‐disubstituted 1,2,3‐triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross‐linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor‐1. NMR and X‐ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole‐bridged peptides also displayed superior half‐lives in liver S9 stability assays compared to disulfide‐bridged peptides. This work establishes a foundation for the application of 1,5‐disubstituted 1,2,3‐triazoles as disulfide mimetics.
Made to measure: Disulfide mimetics are an important tool to overcome the redox instability of disulfide‐rich peptides for therapeutic application. The installation and structural characterisation of a triazole motif (blue) is reported that provides exceptional mimicry of disulfide linkages (yellow). This approach was demonstrated for a series of backbone‐cyclic serine protease inhibitors.</description><subject>Alkynes</subject><subject>Amino Acid Sequence</subject><subject>Backbone</subject><subject>Crystallography</subject><subject>Crystallography, X-Ray</subject><subject>Cyclization</subject><subject>Cycloaddition</subject><subject>disulfide mimetics</subject><subject>Disulfides - chemistry</subject><subject>inhibitors</subject><subject>Linkages</subject><subject>Molecular Mimicry</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Nuclear Magnetic Resonance, Biomolecular</subject><subject>Peptides</subject><subject>Peptides, Cyclic - chemistry</subject><subject>peptidomimetics</subject><subject>Protease inhibitors</subject><subject>Proteinase inhibitors</subject><subject>Ruthenium</subject><subject>Ruthenium - chemistry</subject><subject>Serine</subject><subject>Serine proteinase</subject><subject>Structural analysis</subject><subject>Sunflowers</subject><subject>triazole bridges</subject><subject>Triazoles</subject><subject>Triazoles - chemistry</subject><subject>Trypsin</subject><subject>Trypsin inhibitors</subject><issn>1433-7851</issn><issn>1521-3773</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1LHTEUhkNR6ke77VICbrqZaz7vZJbXW20FbQu165BJTiSSOzMmM8h11Z_gb_SXGLlWwY2rc-A854H3RegLJTNKCDsyXYAZI4wQLrj8gHapZLTidc23yi44r2ol6Q7ay_m68EqR-Ue0wxmriVRkF-nFMMRgzRj6DpvO4T9jmuw4JRPxojNxnUPGvceXKZi7PsLDv_vjFNwVOPwt5Cn64ABfhBWMwWYcOrxc2-LDv2EYyyl_QtvexAyfn-c--nt6crn8UZ3_-n62XJxXVkgiq2YufKMcOC5aYyWxnllBKZ0710Ir58ooyXnDfCNEDcSL1qtWtACcMFaC8330deMdUn8zQR71KmQLMZoO-ilrxkt0wmqlCnr4Br3up1SyFkpQ1ciaUVKo2Yayqc85gddDCiuT1poS_VS9fqpev1RfHg6etVO7AveC_--6AM0GuA0R1u_o9OLn2cmr_BHjV5Cb</recordid><startdate>20200706</startdate><enddate>20200706</enddate><creator>White, Andrew M.</creator><creator>Veer, Simon J.</creator><creator>Wu, Guojie</creator><creator>Harvey, Peta J.</creator><creator>Yap, Kuok</creator><creator>King, Gordon J.</creator><creator>Swedberg, Joakim E.</creator><creator>Wang, Conan K.</creator><creator>Law, Ruby H. 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P. ; Durek, Thomas ; Craik, David J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4505-964f98ded34bac50cf2c41116ddbeb568a853392f9447e0f4bf8b4bee30224353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Alkynes</topic><topic>Amino Acid Sequence</topic><topic>Backbone</topic><topic>Crystallography</topic><topic>Crystallography, X-Ray</topic><topic>Cyclization</topic><topic>Cycloaddition</topic><topic>disulfide mimetics</topic><topic>Disulfides - chemistry</topic><topic>inhibitors</topic><topic>Linkages</topic><topic>Molecular Mimicry</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Nuclear Magnetic Resonance, Biomolecular</topic><topic>Peptides</topic><topic>Peptides, Cyclic - chemistry</topic><topic>peptidomimetics</topic><topic>Protease inhibitors</topic><topic>Proteinase inhibitors</topic><topic>Ruthenium</topic><topic>Ruthenium - chemistry</topic><topic>Serine</topic><topic>Serine proteinase</topic><topic>Structural analysis</topic><topic>Sunflowers</topic><topic>triazole bridges</topic><topic>Triazoles</topic><topic>Triazoles - chemistry</topic><topic>Trypsin</topic><topic>Trypsin inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>White, Andrew M.</creatorcontrib><creatorcontrib>Veer, Simon J.</creatorcontrib><creatorcontrib>Wu, Guojie</creatorcontrib><creatorcontrib>Harvey, Peta J.</creatorcontrib><creatorcontrib>Yap, Kuok</creatorcontrib><creatorcontrib>King, Gordon J.</creatorcontrib><creatorcontrib>Swedberg, Joakim E.</creatorcontrib><creatorcontrib>Wang, Conan K.</creatorcontrib><creatorcontrib>Law, Ruby H. P.</creatorcontrib><creatorcontrib>Durek, Thomas</creatorcontrib><creatorcontrib>Craik, David J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Angewandte Chemie International Edition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>White, Andrew M.</au><au>Veer, Simon J.</au><au>Wu, Guojie</au><au>Harvey, Peta J.</au><au>Yap, Kuok</au><au>King, Gordon J.</au><au>Swedberg, Joakim E.</au><au>Wang, Conan K.</au><au>Law, Ruby H. P.</au><au>Durek, Thomas</au><au>Craik, David J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Application and Structural Analysis of Triazole‐Bridged Disulfide Mimetics in Cyclic Peptides</atitle><jtitle>Angewandte Chemie International Edition</jtitle><addtitle>Angew Chem Int Ed Engl</addtitle><date>2020-07-06</date><risdate>2020</risdate><volume>59</volume><issue>28</issue><spage>11273</spage><epage>11277</epage><pages>11273-11277</pages><issn>1433-7851</issn><eissn>1521-3773</eissn><abstract>Ruthenium‐catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5‐disubstituted 1,2,3‐triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross‐linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor‐1. NMR and X‐ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole‐bridged peptides also displayed superior half‐lives in liver S9 stability assays compared to disulfide‐bridged peptides. This work establishes a foundation for the application of 1,5‐disubstituted 1,2,3‐triazoles as disulfide mimetics.
Made to measure: Disulfide mimetics are an important tool to overcome the redox instability of disulfide‐rich peptides for therapeutic application. The installation and structural characterisation of a triazole motif (blue) is reported that provides exceptional mimicry of disulfide linkages (yellow). This approach was demonstrated for a series of backbone‐cyclic serine protease inhibitors.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>32270580</pmid><doi>10.1002/anie.202003435</doi><tpages>5</tpages><edition>International ed. in English</edition><orcidid>https://orcid.org/0000-0002-7973-7632</orcidid><orcidid>https://orcid.org/0000-0001-5592-5789</orcidid><orcidid>https://orcid.org/0000-0003-4243-8660</orcidid><orcidid>https://orcid.org/0000-0003-0686-227X</orcidid><orcidid>https://orcid.org/0000-0003-4735-6242</orcidid><orcidid>https://orcid.org/0000-0003-0007-6796</orcidid><orcidid>https://orcid.org/0000-0002-9481-1079</orcidid><orcidid>https://orcid.org/0000-0002-9409-5287</orcidid><orcidid>https://orcid.org/0000-0002-7041-9937</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Alkynes Amino Acid Sequence Backbone Crystallography Crystallography, X-Ray Cyclization Cycloaddition disulfide mimetics Disulfides - chemistry inhibitors Linkages Molecular Mimicry NMR Nuclear magnetic resonance Nuclear Magnetic Resonance, Biomolecular Peptides Peptides, Cyclic - chemistry peptidomimetics Protease inhibitors Proteinase inhibitors Ruthenium Ruthenium - chemistry Serine Serine proteinase Structural analysis Sunflowers triazole bridges Triazoles Triazoles - chemistry Trypsin Trypsin inhibitors |
| title | Application and Structural Analysis of Triazole‐Bridged Disulfide Mimetics in Cyclic Peptides |
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